Nitric oxide (NO) is known for its dual physiological role as helpful messenger and harmful intermediate. Nitric oxide is shown to be generated in numerous cell types including macrophages, neutrophils, hepatocytes and endothelial cells. See Hibbs et al, Science, 1987,235,473-476; Rimele et al, J. Pharmacol. Exp. Ther., 1988, 245, 102-111; Curran et al, J. Exp. Med., 1989, 170, 1769-1774; and Plamer et al, Nature, 1987, 327, 524-526; respectively. The chemical reaction responsible for the production of NO is catalyzed by a class of enzymes referred to as nitric oxide synthases (NOS) which convert L-arginine to citrulline and NO. Forstermann et al, Biochemical Pharmacology, 1991,42, 1849-1857. While the role of NO as a signaling molecule in the stimulation of guanylate cyclase is well established, (Monocada et al, Pharmacological Reviews, 1991, 43, 109-142), the origins of its cytoxicity remained unclear.
Recently a body of compelling evidence surfaced which teaches that NO by itself may not be responsible for cell damage (See Absts. of 1st Annual Mtg. of Oxygen Society, Nov. 12-4, 1993, Charleston, S.C., "Nitric Oxide Requires Superoxide to Exert Bactericidal Activity" by L. Brunnelli and J. S. Beckman). Instead a more reactive species, peroxynitrite, produced by the reaction of superoxide and NO, is found to play a role in the cytotoxicity observed with the over-production of NO. Peroxynitrite is known to decompose via a process which is first order in protons. The rate of proton catalyzed decomposition of peroxynitrite (hereinafter "the natural background rate of decay") is understood from its study over a variety of pH ranges (see; Keith et al. J Chem Soc (A), p.90, 1969). When the pH is 7.4 and the temperature is maintained at 37.degree. C., the observed rate for the decomposition of peroxynitrite is 3.6.times.10.sup.-1 sec-i (see Beckman et al. Proc. Natl. Acad. Sci. USA Vol 87, pp1620-1624, 1990). Beckman shows that peroxynitrite decomposition generates a strong oxidant with reactivity similar to hydroxyl radical, as assessed by the oxidation of deoxyribose or dimethyl sulfoxide with the further suggestion that superoxide dismutase protects vascular tissue stimulated to produce superoxide and NO under pathological conditions by preventing the formation of peroxynitrite. See Beckman et al, "Apparent Hydroxyl Radical Production by Peroxynitrite: Implications for Endothelial Injury from Nitric Oxide and Superoxide" in Proc. Natl. Acad. Sci. USA, Vol. 87, pp 1629-1624, February 1990.
Further, it is well established that peroxynitrite decomposes to give the hydroxyl radical and nitrogen dioxide, a potent nitrating agent. Both of these species are potent oxidants shown to react with lipid membrane and sulfhydryl moieties (See Radi et al "Peroxynitrite Oxidation of Sulfhydryls" in The Journal of Biological Chemistry, Vol. 266, No. 7 March 5, pp 4244-4250, 1991).
Hardy et al suggest the interaction of O.sub.2- with nitric oxide forms peroxynitrite or the protonation of O.sub.2- to form perhydroxyl radical is involved in the neutrophil-meditated killing of HAE cells (FASEB Meeting on Apr. 5-9, 1992 in Anaheim, Calif.) and further Hardy et al suggest a role for peroxynitrite in oxidative damage of human endothelial cells (Abstract in the "Experimental Biology" section of FASEB on Mar. 28-Apr. 1, 1993 in New Orleans, La.).
In other words, harmful products from peroxynitrite decomposition is specifically taught by many references.
In addition, it has been shown that the reaction of peroxynitrite with Mn and Fe SOD results in inactivation of the enzyme (See also Radi et al, Arch. Biochem. Biophys., 1991, 288, 481-487). It is now known that peroxynitrite will also inactivate CuZn SOD.
Thus, the effects of the decomposition of peroxynitrite; whether by the generation of damaging decomposition products or inactivation of SOD, in a wide variety of diseases are well documented.
For example, a study assessing the deleterious effects of peroxynitrite on the rat colon is reported by Rachmilewitz et al in "Peroxynitrite-induced Rat Colitis: A New Model of Colonic Inflammation" from Gastroenterology 105 (6) 1993.
Beckman et al in PCT/US91/07894 (corresponding to U.S. Pat. No. 5,277,908) teach, specifically that peroxynitrite is formed by the reaction of superoxide (O.sub.2-) and nitric oxide in tissues subjected to ischemic, inflammatory or septic conditions. Beckman et al link SOD deficiencies and peroxynitrite to amyotrophic lateral sclerosis (ALS) in Nature, Vol 364, 12 August 1993 and Hogg et al and Beckman et al., respectively, present a relationship between peroxynitrite and atherosclerosis in Biochemical Society Transactions, Vol. 21, received Dec. 22, 1992 and in "Extensive Nitration of Protein Tyrosines in Human Atherosclerosis Detected by Immunohistochemistry", Biol Chem. Hoppe-Sevler, Vol. 375, pp 81-88, February 1994. Further, the involvement of peroxynitrite in various disease states is found for lung diseases attributed to cigarette smoke, atherosclerosis, amyotrophic lateral sclerosis, cold-induced brain edema in Chem. Res. Toxicol., Vol. 5, No. 3, 1992 pp 425-431. See also "Cold-induced Brain Edema in Mice" in The Journal of Biological Chemistry, Vol.268, No. 21 Issue of July 25, pp 15394-15398, 1993.
More recently a spinal neuron toxicity assay has been developed by Scherch et al to screen for drugs which block peroxynitrite toxicity. (23rd Annual Meeting of the Society for Neuroscience, Washington, D. D., Nov. 7-12, 1993 and abstracted in Society for Neuroscience Abstracts 19 (1-3) 1993 and Biosis 94:4951.
Further, by preventing inactivation of SOD by reducing the presence of peroxynitrite the present invention also provides enhancement of known physiological benefits of superoxide dismutase in the treatment of diseases based on such benefits. In this regard SOD and its mimics have been shown to be useful in the treatment of diseases for the inhibition of an overproduction of superoxide and nitric oxide. Thus, the present invention relates to the known treatment for diseases by SOD and SOD mimics.
The Beckman et al PCT application also teaches that SODs catalyze the dismutation of the oxygen radical superoxide and provides references which show SOD and variants thereof have been commonly utilized to prevent or reduce oxidation injury in the treatment of stroke and head trauma, myocardial ischemia, abdominal vascular occlusion, cystitis, and a variety of inflammatory conditions. Beckman et al PCT application also recognizes the presence of peroxynitrite in these same disease conditions associated with O.sub.2- without indicating the further improvements of the present invention.
Further teachings to the diseases known to be associated with treatment by SOD or its mimics are found in EP Publication No. 0524161 (EP Appl. No. 92870097) which is incorporated by reference therefor.
Porphyrin complexes are disclosed in U.S. Pat. No. 5,284,674 as valuable diagnostic and therapeutic agents, non-peptide phaeophorbide analogs are disclosed in Japanese Patent Publication Hei 5-331063 as endocerine receptor antagonists, carotenoporphyrins are disclosed in U.S. Pat. No. 5,286,474 to be valuable for locating and visualizing mammalian tumor tissue and similar nitrogen containing macrocycles without a complexed metal are disclosed as cytotoxic agents in U.S. Pat. No. 5,283,255. No metal complexes and their usefulness are shown as now found in the present invention.
Metal complexes are, however, shown to be useful compounds in Derwent Abstract as intermediates in JP05277377-A and MRI agents in U.S. Pat. No. 5,284,944; cyan pigments in U.S. Pat. No. 5,286,592; photoconductive phthalocyanine compositions in U.S. Pat. No. 5,283,146; a recording layer in an optical recording medium in U.S. Pat. No. 5,284,943 and near infrared absorbers and display/recording materials in an abstract for U.S. Pat. No. 5,296,1632.
Iron hemoprotein is disclosed to be an effective agent to bind or oxidize nitric oxide which has a deleterious physiological effect when induced by a cytokine or by endotoxin for the treatment of diseases such as septic shock in PCT application No. PCT/US93/01288 (Publication No. WO 93/16721).
Other complexes and their utilities are disclosed. For example, "Ruthenium Phthalocyanines" are disclosed as water soluble agents for photodynamic cancer Therapy in Platinum Metals Rev., 1995, 39, (1), 14-18; selected metallo-organic complexes are disclosed as treatment of inflammation in U.S. Pat. No. 4,866,054; Porphyrin and phthalocyanine antiviral compositions are disclosed as inhibitors of infection or replication of HIV in U.S. Pat. No. 5,109,016; Manganese meso-tetra(4-sulfonatophenyl)porphine are synthesized and used as tumor-selective MRI contrast agents; an abstract for JP 03273082 teaches peroxide-degrading metal porphyrins for use as antioxidants in the manufacture of foods or other products; U.S. Pat. No. 4,758,429 teaches iron tetraphenyl porphyrin sulfonate acetate for activating magnetic or electrical dipoles in the joint with an alternating electromagnetic field to treat arthritis and non-infectious joint diseases; an abstract of EP 392666 shows a non-toxic labile metal atom or complex such as 1,5,9,13-tetrazacyclohexadecane for use in the treatment of a virus such as HIV. CA 119:203240 discloses selected metalloporphyrins as hypoplycemics are found in French Patent No. 91-6174. Numerous additional references indicate analogous additional uses for metal complexes.
Finally, nitrogen containing selected macrocycles are shown in JPO5331063 as endothelin receptor antagonists for treating and preventing hypertension, acute renal failure, cardiomyopathy and myocardial infarction.